Synthetic Activity Research Articles

Synthetic curcumin analogues present antiflavivirus activity in vitro with potential multiflavivirus activity from a thiazol-ylhydrazone moiety

Synthetic curcumin analogues present antiflavivirus activity in vitro with potential multiflavivirus activity from a thiazol-ylhydrazone moiety

A paralog of Pcc1 is the fifth core subunit of the KEOPS tRNA-modifying complex in Archaea

In Archaea and Eukaryotes, the synthesis of a universal tRNA modification, N6-threonyl-carbamoyl adenosine (t6A), is catalyzed by the KEOPS complex composed of Kae1, Bud32, Cgi121, and Pcc1. A fifth subunit, Gon7, is found only in Fungi and Metazoa. Here, we identify and characterize a fifth KEOPS subunit in Archaea. This protein, dubbed Pcc2, is a paralog of Pcc1 and is widely conserved in Archaea. Pcc1 and Pcc2 form a heterodimer in solution, and show modest sequence conservation but very high structural similarity. The five-subunit archaeal KEOPS does not form dimers but retains robust tRNA binding and t6A synthetic activity. Pcc2 can substitute for Pcc1 but the resulting KEOPS complex is inactive, suggesting a distinct function for the two paralogs. Comparative sequence and structure analyses point to a possible evolutionary link between archaeal Pcc2 and eukaryotic Gon7. Our work indicates that Pcc2 regulates the oligomeric state of the KEOPS complex, a feature that seems to be conserved from Archaea to Eukaryotes.

Mitochondrial uncouplers induce proton leak by activating AAC and UCP1.

Mitochondria generate heat due to H+ leak (IH) across their inner membrane. IH results from the action of long-chain fatty acids (FA) on uncoupling protein 1 (UCP1) in brown fat and ADP/ATP carrier (AAC) in other tissues, but the underlying mechanism is poorly understood. Because no pharmacological activators of IH via UCP1 and AAC are known, IH is induced by protonophores such as 2,4-dinitrophenol (DNP) and cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP) that are thought to increase IH independently of membrane proteins. Protonophores are highly effective in combating obesity, insulin resistance, type II diabetes, and fatty liver in animal models, but because they indiscriminately increase H+ conductance across all biological membranes and have adverse side effects, their use in humans is restricted. Here we report the first direct measurement of IH induced by common protonophores and discover that their mechanism of action in mitochondria was significantly misunderstood. IH induced by DNP and other protonophores depends on AAC and UCP11. Using molecular structures of AAC, we perform a computational analysis to determine the binding sites for protonophores and long-chain FA and find that they overlap with the putative ADP/ATP binding site. We also develop a mathematical model that proposes a mechanism of uncoupler-dependent IH via AAC. Thus, common protonophoric uncouplers emerge as the first synthetic activators of IH via UCP1 and AAC identified to date, paving the way for the development of new and more specific activators of these two proteins.

Molecular taxonomy of nociceptors and pruriceptors.

Molecular taxonomy of nociceptors and pruriceptors.

Synthesis, Fungicidal Activity and Plant Protective Properties of 1,2,3-Thiadiazole and Isothiazole-Based N-acyl-N-arylalaninates.

The addition of active groups of known fungicides, or systemic acquired resistance inducers, into novel compound molecules to search for potential antifungal compounds is a popular and effective strategy. In this work, a new series of N-acyl-N-arylalanines was developed and synthesized, in which 1,2,3-thiadiazol-5-ylcarbonyl or 3,4-dichloroisothiazol-5-ylcarbonyl (fragments from synthetic plant resistance activators tiadinil and isotianil, respectively) and a fragment of N-arylalanine, the toxophoric group of acylalanine fungicides. Several new synthesized compounds have shown moderate antifungal activity against fungi in vitro, such as B. cinerea, R. solani and S. sclerotiorum. In vivo tests against A. brassicicola showed that compound 1d was 92% effective at a concentration of 200 µg/mL, similar to level of tiadinil, a known inducer of systemic resistance. Thus, 1d could be considered a new candidate fungicide for further detailed study. The present results will advance research and influence the search for more promising fungicides for disease control in agriculture.

Synthetic activation of yeast stress response improves secretion of recombinant proteins

Yeasts, such as Pichia pastoris (syn Komagataella spp.), are particularly suitable expression systems for emerging classes of recombinant proteins. Among them, recombinant antibody fragments, such as single-chain variable fragments (scFv) and single-domain antibodies (VHH), are credible alternatives to monoclonal antibodies. The availability of powerful genetic engineering and synthetic biology tools has facilitated improvement of this cell factory to overcome certain limitations. However, cell engineering to improve secretion often remains a trial-and-error approach and improvements are often specific to the protein produced. Where multiple genetic interventions are needed to remove bottlenecks in the process of recombinant protein secretion, this leads to a high number of combinatorial possibilities for creation of new production strains. Therefore, our aim was to exploit whole transcriptional programs (stress response pathways) in order to simplify the strain engineering of new production strains. Indeed, the artificial activation of the general stress response transcription factor Msn4, as well as synthetic versions thereof, could replace the secretion enhancing effect of several cytosolic chaperones. Greater than 4-fold improvements in recombinant protein secretion were achieved by overexpression of MSN4 or synMSN4, either alone or in combination with Hac1 or ER chaperones. With this concept we were able to successfully engineer strains reaching titers of more than 2.5 g/L scFv and 8 g/L VHH in bioreactor cultivations. This increased secretion capacity of different industrially relevant model proteins indicates that MSN4 overexpression most likely represents a general concept to improve recombinant protein production in yeast.

The morphological and functional ultrastructure of cells in pre-implantation embryos.

Cells of pre-implantation embryos are equipped with many morphological and functional systems through which they can synthesize specific proteins and effectively ensure the protection of early embryonic development. Here we present evidence for the existence of these systems in morphologically normal and abnormal bovine blastocyst stage embryos in vivo at the ultrastructural and actin cytoskeleton levels. The appearance of organelles in the trophectoderm (TE) and inner cell mass (ICM) cells, responsible for their synthetic activities and their role in the development of early bovine embryos are described. We point out the importance of endocytic processes and the participation of extracellular vesicles in the formation of intercellular contacts and homeostasis of the embryo microenvironment. Several changes in the ultrastructural morphology of embryos produced by different methods (ICSI, parthenogenetic AC/DC electrical activation, IVF with separated sperm) and freezing/thawed embryos are described. We also show alterations occurred in the organelles after viral contamination of embryos with BHV-1 and BVDV viruses, and in embryos from over-conditioned cows. Recorded changes in organelles and appearance of cellular autophagic structures (vesicles, multivesicular bodies and autophagolysosomes) may negatively affect embryo metabolism and lead to the emergence of pathological processes in TE and ICM cells of preimplantation embryos.

Synthetic Routes and Biological Activities of Chromone Scaffolds: An Overview

The central backbones of natural assets and therapeutic medications are chromone and flavone. Utilizing such preferred chalcone analogs in drug research has shown a successful blueprint, yielding new hits/leads and fast optimization procedures. Chromone can create novel molecules with pharmacological promise, particularly in neurological, inflammatory, infectious diseases, cancer and diabetes. The current perspective focuses mainly on flavones and flavonoids of biological significance, such as chromon-4-one analogs, both synthetic and natural sources. Furthermore, because drug repurposing is now a popular drug discovery strategy, current chromone-based medication repurposing research is discussed. As well the methods utilized to synthesize chromones and their derivatives are described in detail in this review. Since it’s uses in so many pharmacologically active substances, the stiff bicyclic chalcone fraction has been described as a preferred scaffold in drug development, with few instances as therapeutic agents. Due to their photochemical characteristics, chromone analogs are also utilized as scaffolds for creating bioactive molecules and their application in drug development, such as the production of fluorescent probes.

Editorial

Dear colleagues, The year 2022 that passed was, without any doubt, the most difficult and dramatic in the history of modern Ukraine. The country underwent attacks not only on the battlefields, but also on its civilian infrastructure, water and power supplies, resulting in the loss of many lives, inflicting huge migration and immigration waves, and imposing heavy mental pressure on all of its population. Is it possible, and is it sensible to do science in such a situation? Our confident answer is ``yes'', for a couple of reasons. Firstly, scientists contribute to the all-nation defense in their unique way, by helping in solving current problems in: physics and chemistry of new materials and cleaning technologies, aerodynamics and ballistics, as well as in the various applications of the IT technology. Secondly, if there is no science and art in the future, then the question “what people are fighting for?”, attributed to W. Churchill, becomes really topical. At stake is nothing less than a survival and a future rise of the country in a form of normally functioning institution, covering all the relevant aspects and attributes: from the infrastructure and economics all the way to the highly synthetic human activities. Many would imagine that a small-scale journal like ours would not survive in the turbulent times of today. However, despite all the difficulties in financing, intermittent electricity supply, and regular air raid alarms, we, in Condensed Matter Physics journal, continued to work in 2022 and compiled four issues with the research from all over the world. This was achieved with a big help from you all, our colleagues and partners all over the world. During this year we, as never before, felt this support and are eternally grateful for that. You can strongly support our science, our journal, and those Ukrainian scientists who remain in Ukraine, by submitting your research papers to our journal in 2023. Please do so, to ensure the continuity of our scientific traditions and our precious collaboration network! Your CMP team.

Synthetic, spectral, structural and catalytic activities of 3-D metal format/acetate framework materials for CO2 conversion

Copper and nickel polymer bridging by formate/acetate groups has been synthesized and used as substrate size-dependent catalyst for CO2 cycloaddition with epoxides.

Synthetic approaches, modification ability and biological activity of 1,3,4-thiadiazole based [5+5] annelated heterosystems: Mini-review

Condensed bicyclic systems with thiadiazole core being annelated to other five-membered heterocycles such as 1,3-thiazole, imidazole or 1,2,4-triazole occupy prominent place in medicinal chemistry because of their broad spectrum of pharmacological activities. The combination of several heterocycles into a bicyclic system commonly provides much more interest in the enhanced activity profile of its analogs than their parent separate constituents. In this review, we summarized the literature data about the main approaches for obtaining and possible directions of structural modification of the most common 1,3,4-thiadiazole containing [5+5] annelated heterosystems as promising objects for modern medicinal chemistry.

New supramolecules of bis(acylhydrazones)-linked bisphenol sulfide for Alzheimer's: targeting cholinesterases by in vitro and in silico approaches.

In current research, two functional components, i.e., hydrazone and bisphenol sulfide were combined to get useful supramolecules in medicinal chemistry. Herein 25 new 4,4'-thiodiphenol bis-acylhydrazones were synthesized in good to excellent yields. Initially ethyl-2-chloroacetate was reacted with 4,4'-thiodiphenol, which was further reacted with excess hydrazine hydrate to produce 2,2'-((thiobis(4,1-phenylene))bis(oxy))di(acetohydrazide), which was then combined with various aromatic and aliphatic aldehydes to get the desired products (hydrazones, 4a-4y). The synthesized supramolecules were characterized by contemporary spectroscopic techniques such as 1H NMR, 13C NMR, and mass spectroscopy. The synthetic compound's cholinesterase blocking activity was tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes where compounds 4n, and 4h showed excellent inhibitory potential for AChE, while 4b, and 4h, demonstrated most potent inhibition of BChE. The starting compound (SM3) and compounds 4h and SM3 depicted excellent dual inhibitory capabilities for both enzymes. The chemical basis of anticholinesterase activity was investigated using a structure-based molecular docking approach. The biological significance and the ease of synthesis of this class of compounds should be considered in therapeutic development for Alzheimer's disease treatments.

Synthetic Promoter Screening Using Poplar Mesophyll Protoplast Transformation.

Plant protoplasts are useful to study both transcriptional regulation and protein subcellular localization in rapid screens. Protoplast transformation can be used in automated platforms for design-build-test cycles of plant promoters, including synthetic promoters. A notable application of protoplasts comes from recent successes in dissecting synthetic promoter activity with poplar mesophyll protoplasts. For this purpose, we constructed plasmids with TurboGFP driven by a synthetic promoter together with TurboRFP constitutively controlled by a 35S promoter, to monitor transformation efficiency, allowing versatile screening of high numbers of cells by monitoring green fluorescent protein expression in transformed protoplasts. Herein, we introduce a protocol for poplar mesophyll protoplast isolation followed by protoplast transformation and image analysis for the selection of valuable synthetic promoters. Graphical overview.

Remineralization of Demineralized Bone Matrixes with Preserved Fibrillary Structure as a Promising Approach to Obtain Highly Effective Osteoplastic Materials

The development of highly effective osteoplastic materials capable of providing bone tissue regeneration still remains an urgent and unresolved problem. In the presented work, an approach is proposed for the creation of biomimetic materials by the deposition of amorphous calcium phosphates on the surface of a xenogenic bone demineralized matrix under physiological conditions. Adsorption spectroscopy and scanning electron microscopy showed the efficiency of deposition of amorphous calcium phosphates on the trabeculae surface. The additional inclusion of the calcium-binding protein albumin was found to increase the efficiency of CPC adsorption on the trabeculae surface during DBM remineralization in vitro. In the model of heterotopic implantation for 7 weeks the osteoinductive properties of the obtained material were demonstrated, expressed in intrabecular mineralization of bone trabeculae, neovascularization and pronounced synthetic activity of osteoblasts (synthesis and structurization of neocollagen directly on the implanted material). The data obtained in the course of this work will be used to create new highly effective osteoplastic materials.

Feasibility assessment of net zero-energy transformation of building stock using integrated synthetic population, building stock, and power distribution network framework

The transformation to net zero-energy (nZE) building stocks involves harvesting of renewable energy, enhancement of building energy efficiency, incorporation of various supply-side options, and advanced energy management. Although several studies have evaluated the feasibility of nZE for residential areas in cold regions, only a few studies have been conducted on dense urban regions in noncold climate. Additionally, the accommodation of such building stock transformation by the current power distribution network has not been clarified to date. Thus, this study proposes a novel framework integrating synthetic population, activity, building stock, and power distribution network to explore transformation pathways. This was further demonstrated by a case study on a densely populated region covering four cities in Tokyo, Japan. The results signified that complete dissemination of popular energy efficiency measures can reduce the energy demand by 40%. With the reduction in energy demand, nearly nZE condition can be realized only if the building roof area is completely covered by photovoltaics. In particular, one half of the generation would be utilized locally, whereas the remaining would be exported. Moreover, the power distribution network can accommodate the transformation with a slight increase in power distribution loss up to 1% and a modest reinforcement requirement owing to line overloading. Conclusively, this study revealed that the transformation and reinforcement requirement are significantly distinct from those required in cold regions.

Structure optimization of new tumor-selective Passerini α-acyloxy carboxamides as Caspase-3/7 activators

Selective elimination of tumors has always been the mainstay of oncology research. The on-going research underlying the cellular apoptotic mechanisms reveal caspases activation, especially the key effector caspase-3, as a personalized tumor-selective therapeutic strategy. Our continued research protocol has exploited new optimized Passerini α-acyloxy carboxamides as efficient apoptotic inducers via caspase-3/7 dependent mechanism with highly selective anticancer profiles. The adopted design rationale relied on excluding structural alerts of previous leads, while merging various pharmacophoric motifs of natural and synthetic caspase activators via optimized one-pot Passerini reaction conditions. The prepared compounds resulting from Passerini reaction were screened for their cytotoxic activities against colorectal Caco-2 and liver HepG-2 cancer cells compared to normal fibroblasts utilizing MTT assay. Notably, all compounds exhibited promising low-range submicromolar IC50 against the studied cancer cell lines, with outstanding tumor selectivity (SI values up to 266). Hence, they were superior to 5-fluorouracil. Notably, 7a, 7g, and 7j conferred the highest potencies against Caco-2 and HepG-2 cells and were selected for further mechanistic studies. Caspas-3/7 activation assay of the hit compounds and flow cytometric analysis of the treated apoptotic cancer cells demonstrated their significant caspase activation potential (up to 4.2 folds) and apoptotic induction capacities (up to 58.7%). Further assessment of Bcl2 expression was performed being a physiological caspase-3 substrate. Herein, the three studied Passerini adducts were able to downregulate Bcl2 in the treated Caco-2 cells. Importantly, the mechanistic studies results of the three hits echoed their preliminary MTT antiproliferative potencies data highlighting their caspase-3 dependent apoptotic induction. Finally, the in silico predicted physicochemical and pharmacokinetic profiles, as well as ligand efficiency metrics were drug-like.

A Review on Synthetic Approaches and Activities of 1, 2, 4-Triazoles

1, 2, 4-Triazoles and their derivatives have a distinct place in the field of medicinal and pharmaceutical chemistry. These are used as lead compounds for the synthesis of numerous heterocyclic compounds which possess diverse biological activities and play pivotal roles. This review covers the latest literature and knowledge on the synthetic procedures for various triazoles derivatives, their activities and pharmacological applications. The synthetic routes of 1, 2, 4-triazole compounds as well as their pharmacological properties have been described. The review focuses intensively on two methods: cyclo-addition reaction in the syntheses of various 1, 5-dialky-1H-1, 2, 4-triazole derivatives from the reactive cumulenes with the nitrile precursors as well as the microwave irradiation method.

763 ACTIVATION OF SIRT1 ATTENUATES VASCULAR DYSFUNCTION AND THROMBOSIS IN MTHFR DEFICIENCY

Abstract Beyond well-assessed risk factors, cardiovascular events could be also associated with the presence of epigenetic and genetic alterations, such as the methylenetetrahydrofolate-reductase (MTHFR) C677T polymorphism. This gene variant is related to increased circulating levels of homocysteine (Hcy) and cardiovascular risk. However, heterozygous carriers have an augmented risk of cardiovascular accidents independently from normal Hcy levels, suggesting the presence of additional deregulated processes in MTHFR C677T carriers. Here we hypothesize that targeting Sirtuin 1 (SIRT1) could be an alternative mechanism to control the cardiovascular risk associated to MTHFR deficiency condition. Flow Mediated Dilatation (FMD) and light transmission aggregometry assay were performed in subjects carrying MTHFR C677T allele after administration of resveratrol, the most powerful natural clinical usable compound that owns SIRT1 activating properties. MTHFR C677T carriers with normal Hcy levels revealed endothelial dysfunction and enhanced platelet aggregation associated with SIRT1 downregulation. SIRT1 activity stimulation by resveratrol intake was able to override these abnormalities without affecting Hcy levels. Impaired endothelial function, bleeding time, and wire-induced thrombus formation were rescued in a heterozygous Mthfr-deficient (Mthfr+/-) mouse model after resveratrol treatment. Using a cell-based high-throughput multiplexed screening (HTS) assay, a novel selective synthetic SIRT1 activator, namely ISIDE11, was identified. Ex vivo and in vivo treatment of Mthfr+/- mice with ISIDE11 rescues endothelial vasorelaxation and reduces wire-induced thrombus formation, effects that were abolished by SIRT1 inhibitor. Moreover, platelets from MTHFR C677T allele carriers treated with ISIDE11 showed normalization of their typical hyper-reactivity. These results candidate SIRT1 activation as a new therapeutic strategy to contain cardio and cerebrovascular events in MTHFR carriers.

A Comprehensive Review on Synthetic Approaches and Biological Activities of 1,3,4-oxadiazole

Abstract:Among the large variety of nitrogen and oxygen heterocycles, 1,3,4-oxadiazole scaffold has attracted considerable attention owing to its ability to perform an extensive range of pharmacological actions. Therefore, significant efforts of organic chemists have been directed towards the construction of new drug candidates containing 1,3,4-oxadiazole subunits connected to a known pharmaceutical or a potential pharmacophore. This paper highlights recent publications on the various synthesis techniques of 1,3,4-oxadiazole and related compounds over the previous ten years (2011–2021). The purpose of this review is to present several ways for synthesizing oxadiazole. These heterocyclics are formed mainly by the cyclization reactions of various reactants under diverse conditions. A high priority is given to these heterocyclics in literature investigations due to their pharmacological significance, such as their anticonvulsant, anticancer, antioxidant, antiinflammatory, antibacterial, antidiabetic activities, etc.

Bioactivities of isolated and synthetic riparins of Aniba riparia (NEES) MEZ (LAURACEAE): A brief review

Aniba riparia (Nees) Mez of the Lauraceae family, is a medicinal plant native to the Amazon region and commonly used as a spice. Chemical analyses carried out in 1982 on the leaves of A. riparia revealed the presence of a special group of alkamides called riparins. Subsequently, analogs were synthesized from isolated riparins. Studies have reported useful biological activities for pharmacological applications from natural and synthetic riparins, including anxiolytic, antidepressant, antinociceptive, myorelaxant, antioxidant, antiparasitic, cytotoxic, antitumor, anti-inflammatory, antifungal, and antibacterial activities against Gram-positive and Gram-negative bacteria. This review aims to coherently unify the data obtained from several studies on the bioactivities of natural and synthetic riparin molecules, highlighting recent advances in the understanding of these properties. • Bioactivities of Riparins have been demonstrated by in vitro assays in animal models such as rodents. • These activities have emphasis on anxiolytic, antidepressant, antinociceptive, and many other activities. • Further studies are needed to understand the possible mechanisms of action of these molecules. • Further studies are also necessary to address safety issues in order to develop possible pharmacological and therapeutic agents.